Radiofrequency ablation: mechanisms and clinical applications

Abstract

Radiofrequency ablation (RFA), a form of thermal ablation, employs localized heat to induce protein denaturation in tissue cells, resulting in cell death. It has emerged as a viable treatment option for patients who are ineligible for surgery in various diseases, particularly liver cancer and other tumor-related conditions. In addition to directly eliminating tumor cells, RFA also induces alterations in the infiltrating cells within the tumor microenvironment (TME), which can significantly impact treatment outcomes. Moreover, incomplete RFA (iRFA) may lead to tumor recurrence and metastasis. The current challenge is to enhance the efficacy of RFA by elucidating its underlying mechanisms. This review discusses the clinical applications of RFA in treating various diseases and the mechanisms that contribute to the survival and invasion of tumor cells following iRFA, including the roles of heat shock proteins, hypoxia, and autophagy. Additionally, we analyze‌ the changes occurring in infiltrating cells within the TME after iRFA. Finally, we provide a comprehensive summary of clinical trials involving RFA in conjunction with other treatment modalities in the field of cancer therapy, aiming to offer novel insights and references for improving the effectiveness of RFA.

Keywords

colorectal cancer liver metastases / combination therapies / hepatocellular carcinoma / incomplete radiofrequency ablation / tumor microenvironment

References

[1] d’Arsonval, MA. Action physiologique des courants alternatifs. CR Soc Biol. 1891; 43: 283-286.

[2] Buscarini E, Savoia A, Brambilla G, et al. Radiofrequency thermal ablation of liver tumors. Eur Radiol. 2005; 15(5): 884-894.

[3] Lai EC, Tang CN. Radiofrequency ablation versus hepatic resection for hepatocellular carcinoma within the Milan criteria–a comparative study. Int J Surg. 2013; 11(1): 77-80.

[4] Hocquelet A, Balageas P, Laurent C, et al. Radiofrequency ablation versus surgical resection for hepatocellular carcinoma within the Milan criteria: A study of 281 Western patients. Int J Hyperthermia. 2015; 31(7): 749-757.

[5] Takayama T, Hasegawa K, Izumi N, et al. Surgery versus radiofrequency ablation for small hepatocellular carcinoma: a randomized controlled trial (SURF trial). Liver Cancer. 2022; 11(3): 209-218.

[6] Lau WY, Lai EC. The current role of radiofrequency ablation in the management of hepatocellular carcinoma: a systematic review. Ann Surg. 2009; 249(1): 20-25.

[7] Imai K, Allard MA, Castro Benitez C, et al. Long-term outcomes of radiofrequency ablation combined with hepatectomy compared with hepatectomy alone for colorectal liver metastases. Br J Surg. 2017; 104(5): 570-579.

[8] Goldberg SN, Gazelle GS, Mueller PR. Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance. AJR Am J Roentgenol. 2000; 174(2): 323-331.

[9] Higgins H, Berger DL. RFA for liver tumors: does it really work? Oncologist. 2006; 11(7): 801-808.

[10] Curley SA. Radiofrequency ablation of malignant liver tumors. Oncologist. 2001; 6(1): 14-23.

[11] Hanna NN. Radiofrequency ablation of primary and metastatic hepatic malignancies. Clin Colorectal Cancer. 2004; 4(2): 92-100.

[12] Ishikawa T, Kubota T, Horigome R, et al. Radiofrequency ablation during continuous saline infusion can extend ablation margins. World J Gastroenterol. 2013; 19(8): 1278-1282.

[13] Izzo F, Granata V, Grassi R, et al. Radiofrequency Ablation and Microwave Ablation in Liver Tumors: An Update. Oncologist. 2019; 24(10): e990-e1005.

[14] Regier M, Chun F. Thermal ablation of renal tumors: indications, techniques and results. Dtsch Arztebl Int. 2015; 112(24): 412-418.

[15] Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern EF, Goldberg SN. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology. 2003; 226(2): 441-451.

[16] Buscarini E, Buscarini L. Radiofrequency thermal ablation with expandable needle of focal liver malignancies: complication report. Eur Radiol. 2004; 14(1): 31-37.

[17] Mertyna P, Hines-Peralta A, Liu ZJ, Halpern E, Goldberg W, Goldberg SN. Radiofrequency ablation: variability in heat sensitivity in tumors and tissues. J Vasc Interv Radiol. 2007; 18(5): 647-654.

[18] Thompson SM, Callstrom MR, Butters KA, et al. Heat stress induced cell death mechanisms in hepatocytes and hepatocellular carcinoma: in vitro and in vivo study. Lasers Surg Med. 2014; 46(4): 290-301.

[19] Tong Y, Yang H, Xu X, et al. Effect of a hypoxic microenvironment after radiofrequency ablation on residual hepatocellular cell migration and invasion. Cancer Sci. 2017; 108(4): 753-762.

[20] Lee J, Lee Y, Xu L, White R, Sullenger BA. Differential induction of immunogenic cell death and interferon expression in cancer cells by structured ssRNAs. Mol Ther. 2017; 25(6): 1295-1305.

[21] Lin SM. Local ablation for hepatocellular carcinoma in taiwan. Liver Cancer. 2013; 2(2): 73-83.

[22] Zhao Z, Wu J, Liu X, et al. Insufficient radiofrequency ablation promotes proliferation of residual hepatocellular carcinoma via autophagy. Cancer Lett. 2018; 421: 73-81.

[23] Ruzzenente A, Manzoni GD, Molfetta M, et al. Rapid progression of hepatocellular carcinoma after radiofrequency ablation. World J Gastroenterol. 2004; 10(8): 1137-1140.

[24] Obara K, Matsumoto N, Okamoto M, et al. Insufficient radiofrequency ablation therapy may induce further malignant transformation of hepatocellular carcinoma. Hepatol Int. 2008; 2(1): 116-123.

[25] Shi L, Wang J, Ding N, et al. Inflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy. Nat Commun. 2019; 10(1): 5421.

[26] Fan H, Wang X, Qu J, et al. Periprocedural risk factors for incomplete radiofrequency ablation of liver metastases from colorectal cancer: a single-center retrospective analysis. Int J Hyperthermia. 2021; 38(1): 985-994.

[27] Komorizono Y, Oketani M, Sako K, et al. Risk factors for local recurrence of small hepatocellular carcinoma tumors after a single session, single application of percutaneous radiofrequency ablation. Cancer. 2003; 97(5): 1253-1262.

[28] Hori T, Nagata K, Hasuike S, et al. Risk factors for the local recurrence of hepatocellular carcinoma after a single session of percutaneous radiofrequency ablation. J Gastroenterol. 2003; 38(10): 977-981.

[29] Künzli BM, Abitabile P, Maurer CA. Radiofrequency ablation of liver tumors: actual limitations and potential solutions in the future. World J Hepatol. 2011; 3(1): 8-14.

[30] Veltri A, Guarnieri T, Gazzera C, et al. Long-term outcome of radiofrequency thermal ablation (RFA) of liver metastases from colorectal cancer (CRC): size as the leading prognostic factor for survival. Radiol Med. 2012; 117(7): 1139-1151.

[31] Lu DS, Yu NC, Raman SS, et al. Radiofrequency ablation of hepatocellular carcinoma: treatment success as defined by histologic examination of the explanted liver. Radiology. 2005; 234(3): 954-960.

[32] Lu DS, Raman SS, Limanond P, et al. Influence of large peritumoral vessels on outcome of radiofrequency ablation of liver tumors. J Vasc Interv Radiol. 2003; 14(10): 1267-1274.

[33] Wang CC, Kao JH. Artificial ascites is feasible and effective for difficult-to-ablate hepatocellular carcinoma. Hepatol Int. 2015; 9(4): 514-519.

[34] Odisio BC, Yamashita S, Huang SY, et al. Local tumour progression after percutaneous ablation of colorectal liver metastases according to RAS mutation status. Br J Surg. 2017; 104(6): 760-768.

[35] Teng W, Liu KW, Lin CC, et al. Insufficient ablative margin determined by early computed tomography may predict the recurrence of hepatocellular carcinoma after radiofrequency ablation. Liver Cancer. 2015; 4(1): 26-38.

[36] Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med. 2009; 360(22): 2277-2288.

[37] Leclercq P, Bisschops R. Optimizing outcomes with radiofrequency ablation of Barrett’s esophagus: candidates, efficacy and durability. Gastrointest Endosc Clin N Am. 2021; 31(1): 131-154.

[38] Pech O, May A, Manner H, et al. Long-term efficacy and safety of endoscopic resection for patients with mucosal adenocarcinoma of the esophagus. Gastroenterology. 2014; 146(3): 652-660.e1.

[39] Cucchetti A, Piscaglia F, Cescon M, et al. Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma. J Hepatol. 2013; 59(2): 300-307.

[40] Huang J, Yan L, Cheng Z, et al. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg. 2010; 252(6): 903-912.

[41] Cheung W, Kavnoudias H, Roberts S, Szkandera B, Kemp W, Thomson KR. Irreversible electroporation for unresectable hepatocellular carcinoma: initial experience and review of safety and outcomes. Technol Cancer Res Treat. 2013; 12(3): 233-241.

[42] Cannon R, Ellis S, Hayes D, Narayanan G, Martin RC, 2nd. Safety and early efficacy of irreversible electroporation for hepatic tumors in proximity to vital structures. J Surg Oncol. 2013; 107(5): 544-549.

[43] Frühling P, Nilsson A, Duraj F, Haglund U, Noré A. Single-center nonrandomized clinical trial to assess the safety and efficacy of irreversible electroporation (IRE) ablation of liver tumors in humans: Short to mid-term results. Eur J Surg Oncol. 2017; 43(4): 751-757.

[44] Roayaie S, Jibara G, Tabrizian P, et al. The role of hepatic resection in the treatment of hepatocellular cancer. Hepatology. 2015; 62(2): 440-451.

[45] Abouassaly R, Lane BR, Novick AC. Active surveillance of renal masses in elderly patients. J Urol. 2008; 180(2):505-8; discussion 508-509.

[46] Chen DY, Uzzo RG. Optimal management of localized renal cell carcinoma: surgery, ablation, or active surveillance. J Natl Compr Canc Netw. 2009; 7(6): 635-642; quiz 643.

[47] Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC. Treatment of stage I and II non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013; 143(5 Suppl): e278S-e313S.

[48] Abtin F, De Baere T, Dupuy DE, et al. Updates on current role and practice of lung ablation. J Thorac Imaging. 2019; 34(4): 266-277.

[49] Kim JH, Won HJ, Shin YM, Kim KA, Kim PN. Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AJR Am J Roentgenol. 2011; 196(2): W205-W209.

[50] Edeline J, Lamarca A, McNamara MG, et al. Locoregional therapies in patients with intrahepatic cholangiocarcinoma: a systematic review and pooled analysis. Cancer Treat Rev. 2021; 99: 102258.

[51] Carrafiello G, Laganà D, Cotta E, et al. Radiofrequency ablation of intrahepatic cholangiocarcinoma: preliminary experience. Cardiovasc Intervent Radiol. 2010; 33(4): 835-839.

[52] Bagla S, Sayed D, Smirniotopoulos J, et al. Multicenter prospective clinical series evaluating radiofrequency ablation in the treatment of painful spine metastases. Cardiovasc Intervent Radiol. 2016; 39(9): 1289-1297.

[53] Leitao MM, Brennan MF, Hensley M, et al. Surgical resection of pulmonary and extrapulmonary recurrences of uterine leiomyosarcoma. Gynecol Oncol. 2002; 87(3): 287-294.

[54] Shady W, Petre EN, Gonen M, et al. Percutaneous radiofrequency ablation of colorectal cancer liver metastases: factors affecting outcomes–a 10-year experience at a single center. Radiology. 2016; 278(2): 601-611.

[55] de Baère T, Aupérin A, Deschamps F, et al. Radiofrequency ablation is a valid treatment option for lung metastases: experience in 566 patients with 1037 metastases. Ann Oncol. 2015; 26(5): 987-991.

[56] Solbiati L, Ahmed M, Cova L, Ierace T, Brioschi M, Goldberg SN. Small liver colorectal metastases treated with percutaneous radiofrequency ablation: local response rate and long-term survival with up to 10-year follow-up. Radiology. 2012; 265(3): 958-968.

[57] Mariani P, Almubarak MM, Kollen M, et al. Radiofrequency ablation and surgical resection of liver metastases from uveal melanoma. Eur J Surg Oncol. 2016; 42(5): 706-712.

[58] Taner T, Atwell TD, Zhang L, et al. Adjunctive radiofrequency ablation of metastatic neuroendocrine cancer to the liver complements surgical resection. HPB (Oxford). 2013; 15(3): 190-195.

[59] Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018; 179(4): G1-g46.

[60] Ilaslan H, Schils J, Joyce M, Marks K, Sundaram M. Radiofrequency ablation: another treatment option for local control of desmoid tumors. Skeletal Radiol. 2010; 39(2): 169-173.

[61] Koelblinger C, Strauss S, Gillams A. Outcome after radiofrequency ablation of sarcoma lung metastases. Cardiovasc Intervent Radiol. 2014; 37(1): 147-153.

[62] Abtin F, Quirk MT, Suh RD, et al. Percutaneous cryoablation for the treatment of recurrent malignant pleural mesothelioma: safety, early-term efficacy, and predictors of local recurrence. J Vasc Interv Radiol. 2017; 28(2): 213-221.

[63] Hakimé A, Le Cesne A, Deschamps F, et al. A role for adjuvant RFA in managing hepatic metastases from gastrointestinal stromal tumors (GIST) after treatment with targeted systemic therapy using kinase inhibitors. Cardiovasc Intervent Radiol. 2014; 37(1): 132-139.

[64] Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the american thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016; 26(1): 1-133.

[65] Krajciova J, Vackova Z, Spicak J, Martinek J. Radiofrequency ablation for Barrett’s esophagus-related neoplasia. Minerva Chir. 2018; 73(4): 366-377.

[66] Livraghi T. Single HCC smaller than 2 cm: surgery or ablation: interventional oncologist’s perspective. J Hepatobiliary Pancreat Sci. 2010; 17(4): 425-429.

[67] Lee JM, Jin GY, Goldberg SN, et al. Percutaneous radiofrequency ablation for inoperable non-small cell lung cancer and metastases: preliminary report. Radiology. 2004; 230(1): 125-134.

[68] Joseph JP, Rajappan K. Radiofrequency ablation of cardiac arrhythmias: past, present and future. Qjm. 2012; 105(4): 303-314.

[69] Tzeis S, Gerstenfeld EP, Kalman J, et al. 2024 European Heart Rhythm Association/Heart Rhythm Society/Asia Pacific Heart Rhythm Society/Latin American Heart Rhythm Society expert consensus statement on catheter and surgical ablation of atrial fibrillation. Europace. 2024; 26(4): euae043.

[70] Stevenson WG, Tedrow UB, Reddy V, et al. Infusion needle radiofrequency ablation for treatment of refractory ventricular arrhythmias. J Am Coll Cardiol. 2019; 73(12): 1413-1425.

[71] Lawrenz T, Borchert B, Leuner C, et al. Endocardial radiofrequency ablation for hypertrophic obstructive cardiomyopathy: acute results and 6 months’ follow-up in 19 patients. J Am Coll Cardiol. 2011; 57(5): 572-576.

[72] Long X, Deng S, Liu W, et al. Transcoronary radiofrequency ablation for obstructive hypertrophic cardiomyopathy: a feasibility study. Eur Heart J. 2024; 45(3): 233-235.

[73] Long X, Cai D, Tan H, et al. Transcoronary radiofrequency ablation: a novel closure strategy without implantation for coronary artery fistula. JACC Cardiovasc Interv. 2023; 16(6): 727-729.

[74] Mehra NS, Goel K, Asirvatham SJ, Rihal CS. Right ventriculocutaneous fistula treated with radiofrequency ablation. JACC Cardiovasc Interv. 2019; 12(17): 1737-1738.

[75] Pappone C, Brugada J, Vicedomini G, et al. Electrical substrate elimination in 135 consecutive patients with Brugada syndrome. Circ Arrhythm Electrophysiol. 2017; 10(5): e005053.

[76] McCarty TR, Rustagi T. New indications for endoscopic radiofrequency ablation. Clin Gastroenterol Hepatol. 2018; 16(7): 1007-1017.

[77] McCarty TR, Rustagi T. Comparative effectiveness and safety of radiofrequency ablation versus argon plasma coagulation for treatment of gastric antral vascular ectasia: a systematic review and meta-analysis. J Clin Gastroenterol. 2019; 53(8): 599-606.

[78] Rustagi T, Corbett FS, Mashimo H. Treatment of chronic radiation proctopathy with radiofrequency ablation (with video). Gastrointest Endosc. 2015; 81(2): 428-436.

[79] Marin FS, Hallit R, Coriat R, Chaussade S, Prat F, Barret M. Successful treatment of hemorrhagic radiation esophagitis with radiofrequency ablation. Endoscopy. 2022; 54(S 02): E830-e831.

[80] Han S, Krishna SG, Runge TM. Radiofrequency ablation for hemostasis of an intraductal visible vessel. Clin Gastroenterol Hepatol. 2023; 21(7): A45-a46.

[81] Li Z, Zhou B, Zhang N, Wang S, Meng H. Application of radiofrequency ablation in duodenal mucosal reconstruction. Endoscopy. 2023; 55(S 01): E959-e960.

[82] Li G, Zhang Y, Tian L, Pan J. Radiofrequency ablation reduces pain for knee osteoarthritis: a meta-analysis of randomized controlled trials. Int J Surg. 2021; 91: 105951.

[83] Cohen SP, Bhaskar A, Bhatia A, et al. Consensus practice guidelines on interventions for lumbar facet joint pain from a multispecialty, international working group. Reg Anesth Pain Med. 2020; 45(6): 424-467.

[84] Schneider BJ, Doan L, Maes MK, Martinez KR, Gonzalez Cota A, Bogduk N. Systematic review of the effectiveness of lumbar medial branch thermal radiofrequency neurotomy, stratified for diagnostic methods and procedural technique. Pain Med. 2020; 21(6): 1122-1141.

[85] Jung SL, Baek JH, Lee JH, et al. Efficacy and safety of radiofrequency ablation for benign thyroid nodules: a prospective multicenter study. Korean J Radiol. 2018; 19(1): 167-174.

[86] Radzina M, Cantisani V, Rauda M, et al. Update on the role of ultrasound guided radiofrequency ablation for thyroid nodule treatment. Int J Surg. 2017; 41 Suppl 1: S82-s93.

[87] Andrade JG, Champagne J, Dubuc M, et al. Cryoballoon or radiofrequency ablation for atrial fibrillation assessed by continuous monitoring: a randomized clinical trial. Circulation. 2019; 140(22): 1779-1788.

[88] Kim HJ, Cho SJ, Baek JH, Suh CH. Efficacy and safety of thermal ablation for autonomously functioning thyroid nodules: a systematic review and meta-analysis. Eur Radiol. 2021; 31(2): 605-615.

[89] Tang X, Cao F, Ma W, et al. Cancer cells resist hyperthermia due to its obstructed activation of caspase 3. Rep Pract Oncol Radiother. 2020; 25(3): 323-326.

[90] Schueller G, Kettenbach J, Sedivy R, et al. Heat shock protein expression induced by percutaneous radiofrequency ablation of hepatocellular carcinoma in vivo. Int J Oncol. 2004; 24(3): 609-613.

[91] Yang WL, Nair DG, Makizumi R, et al. Heat shock protein 70 is induced in mouse human colon tumor xenografts after sublethal radiofrequency ablation. Ann Surg Oncol. 2004; 11(4): 399-406.

[92] Kregel KC. Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol (1985). 2002; 92(5): 2177-2186.

[93] Hall DM, Xu L, Drake VJ, et al. Aging reduces adaptive capacity and stress protein expression in the liver after heat stress. J Appl Physiol (1985). 2000; 89(2): 749-759.

[94] Kiang JG, Tsokos GC. Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol Ther. 1998; 80(2): 183-201.

[95] Benjamin IJ, McMillan DR. Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease. Circ Res. 1998; 83(2): 117-132.

[96] Duan X, Zhou G, Zheng C, et al. Heat shock protein 70 expression and effect of combined transcatheter arterial embolization and radiofrequency ablation in the rabbit VX2 liver tumour model. Clin Radiol. 2014; 69(2): 186-193.

[97] Rai R, Richardson C, Flecknell P, Robertson H, Burt A, Manas DM. Study of apoptosis and heat shock protein (HSP) expression in hepatocytes following radiofrequency ablation (RFA). J Surg Res. 2005; 129(1): 147-151.

[98] Wang X, Chen M, Zhou J, Zhang X. HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy (review). Int J Oncol. 2014; 45(1): 18-30.

[99] Ikwegbue PC, Masamba P, Oyinloye BE, Kappo AP. roles of heat shock proteins in apoptosis, oxidative stress, human inflammatory diseases, and cancer. Pharmaceuticals (Basel). 2017; 11(1)

[100] Wang B, Lan T, Xiao H, et al. The expression profiles and prognostic values of HSP70s in hepatocellular carcinoma. Cancer Cell Int. 2021; 21(1): 286.

[101] Hut HM, Kampinga HH, Sibon OC. Hsp70 protects mitotic cells against heat-induced centrosome damage and division abnormalities. Mol Biol Cell. 2005; 16(8): 3776-3785.

[102] Nakahata K, Miyakoda M, Suzuki K, Kodama S, Watanabe M. Heat shock induces centrosomal dysfunction, and causes non-apoptotic mitotic catastrophe in human tumour cells. Int J Hyperthermia. 2002; 18(4): 332-343.

[103] Su T, Liao J, Dai Z, et al. Stress-induced phosphoprotein 1 mediates hepatocellular carcinoma metastasis after insufficient radiofrequency ablation. Oncogene. 2018; 37(26): 3514-3527.

[104] Ahmed M, Kumar G, Gourevitch S, et al. Radiofrequency ablation (RFA)-induced systemic tumor growth can be reduced by suppression of resultant heat shock proteins. Int J Hyperthermia. 2018; 34(7): 934-942.

[105] Sun C, Bai M, Ke W, Wang X, Zhao X, Lu Z. The HSP90 inhibitor, XL888, enhanced cell apoptosis via downregulating STAT3 after insufficient radiofrequency ablation in hepatocellular carcinoma. Life Sci. 2021; 282: 119762.

[106] Jiang X, Maruyama J, Iwasa H, Arimoto-Matsuzaki K, Nishina H, Hata Y. Heat shock induces the nuclear accumulation of YAP1 via SRC. Exp Cell Res. 2021; 399(1): 112439.

[107] Luo M, Meng Z, Moroishi T, et al. Heat stress activates YAP/TAZ to induce the heat shock transcriptome. Nat Cell Biol. 2020; 22(12): 1447-1459.

[108] Barna J, Csermely P, Vellai T. Roles of heat shock factor 1 beyond the heat shock response. Cell Mol Life Sci. 2018; 75(16): 2897-2916.

[109] B’Chir W, Maurin AC, Carraro V, et al. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013; 41(16): 7683-7699.

[110] Llovet JM, De Baere T, Kulik L, et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021; 18(5): 293-313.

[111] Ali MR, Ali HR, Rankin CR, El-Sayed MA. Targeting heat shock protein 70 using gold nanorods enhances cancer cell apoptosis in low dose plasmonic photothermal therapy. Biomaterials. 2016; 102: 1-8.

[112] Nijkamp MW, van der Bilt JD, de Bruijn MT, et al. Accelerated perinecrotic outgrowth of colorectal liver metastases following radiofrequency ablation is a hypoxia-driven phenomenon. Ann Surg. 2009; 249(5): 814-823.

[113] Kong J, Kong L, Kong J, et al. After insufficient radiofrequency ablation, tumor-associated endothelial cells exhibit enhanced angiogenesis and promote invasiveness of residual hepatocellular carcinoma. J Transl Med. 2012; 10: 230.

[114] Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer. 2014; 14(6): 430-439.

[115] Nijkamp MW, Hoogwater FJ, Steller EJ, et al. CD95 is a key mediator of invasion and accelerated outgrowth of mouse colorectal liver metastases following radiofrequency ablation. J Hepatol. 2010; 53(6): 1069-1077.

[116] Liu Z, Dai H, Jia G, Li Y, Liu X, Ren W. Insufficient radiofrequency ablation promotes human hepatoma SMMC7721 cell proliferation by stimulating vascular endothelial growth factor overexpression. Oncol Lett. 2015; 9(4): 1893-1896.

[117] Tan L, Chen S, Wei G, et al. Sublethal heat treatment of hepatocellular carcinoma promotes intrahepatic metastasis and stemness in a VEGFR1-dependent manner. Cancer Lett. 2019; 460: 29-40.

[118] Ham SJ, Choi Y, Lee SI, et al. Enhanced efficacy of radiofrequency ablation for hepatocellular carcinoma using a novel vascular disrupting agent, CKD-516. Hepatol Int. 2017; 11(5): 446-451.

[119] Dong S, Li Z, Kong J, Wu S, Gao J, Sun W. Arsenic trioxide inhibits angiogenesis of hepatocellular carcinoma after insufficient radiofrequency ablation via blocking paracrine angiopoietin-1 and angiopoietin-2. Int J Hyperthermia. 2022; 39(1): 888-896.

[120] Digiacomo G, Fumarola C, La Monica S, et al. Simultaneous combination of the CDK4/6 inhibitor palbociclib with regorafenib induces enhanced anti-tumor effects in hepatocarcinoma cell lines. Front Oncol. 2020; 10: 563249.

[121] Xu M, Zheng YL, Xie XY, et al. Sorafenib blocks the HIF-1α/VEGFA pathway, inhibits tumor invasion, and induces apoptosis in hepatoma cells. DNA Cell Biol. 2014; 33(5): 275-281.

[122] Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990; 82(1): 4-6.

[123] Falchook GS, Wheler JJ, Naing A, et al. Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab. Oncotarget. 2014; 5(21): 10280-10292.

[124] Bussolati B, Deambrosis I, Russo S, Deregibus MC, Camussi G. Altered angiogenesis and survival in human tumor-derived endothelial cells. Faseb j. 2003; 17(9): 1159-1161.

[125] Knipe L, Meli A, Hewlett L, et al. A revised model for the secretion of tPA and cytokines from cultured endothelial cells. Blood. 2010; 116(12): 2183-2191.

[126] Coenen DM, Mastenbroek TG, Cosemans J. Platelet interaction with activated endothelium: mechanistic insights from microfluidics. Blood. 2017; 130(26): 2819-2828.

[127] Kong J, Yao C, Dong S, et al. ICAM-1 activates platelets and promotes endothelial permeability through VE-cadherin after insufficient radiofrequency ablation. Adv Sci (Weinh). 2021; 8(4): 2002228.

[128] Ke S, Ding XM, Kong J, et al. Low temperature of radiofrequency ablation at the target sites can facilitate rapid progression of residual hepatic VX2 carcinoma. J Transl Med. 2010; 8: 73.

[129] Spina A, De Pasquale V, Cerulo G, et al. HGF/c-MET axis in tumor microenvironment and metastasis formation. Biomedicines. 2015; 3(1): 71-88.

[130] Venepalli NK, Goff L. Targeting the HGF-cMET axis in hepatocellular carcinoma. Int J Hepatol. 2013; 2013: 341636.

[131] Markezana A, Goldberg SN, Kumar G, et al. Incomplete thermal ablation of tumors promotes increased tumorigenesis. Int J Hyperthermia. 2021; 38(1): 263-272.

[132] Duan XH, Li H, Han XW, et al. Upregulation of IL-6 is involved in moderate hyperthermia induced proliferation and invasion of hepatocellular carcinoma cells. Eur J Pharmacol. 2018; 833: 230-236.

[133] Ahmed M, Kumar G, Moussa M, et al. Hepatic radiofrequency ablation-induced stimulation of distant tumor growth is suppressed by c-Met inhibition. Radiology. 2016; 279(1): 103-117.

[134] Qi X, Yang M, Ma L, et al. Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response. J Immunother Cancer. 2020; 8(2): e001038.

[135] Erös de Bethlenfalva-Hora C, Mertens JC, Piguet AC, et al. Radiofrequency ablation suppresses distant tumour growth in a novel rat model of multifocal hepatocellular carcinoma. Clin Sci (Lond). 2014; 126(3): 243-252.

[136] Liao H, Ahmed M, Markezana A, et al. Thermal ablation induces transitory metastatic growth by means of the STAT3/c-Met molecular pathway in an intrahepatic colorectal cancer mouse model. Radiology. 2020; 294(2): 464-472.

[137] Ahmed M, Kumar G, Navarro G, et al. Systemic siRNA nanoparticle-based drugs combined with radiofrequency ablation for cancer therapy. PLoS One. 2015; 10(7): e0128910.

[138] Yoshida S, Kornek M, Ikenaga N, et al. Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma. Hepatology. 2013; 58(5): 1667-1680.

[139] Giannelli G, Koudelkova P, Dituri F, Mikulits W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol. 2016; 65(4): 798-808.

[140] Iwahashi S, Shimada M, Utsunomiya T, et al. Epithelial-mesenchymal transition-related genes are linked to aggressive local recurrence of hepatocellular carcinoma after radiofrequency ablation. Cancer Lett. 2016; 375(1): 47-50.

[141] Li G, Kong J, Dong S, Niu H, Wu S, Sun W. Circular BANP knockdown inhibits the malignant progression of residual hepatocellular carcinoma after insufficient radiofrequency ablation. Chin Med J (Engl). 2022.

[142] Wang H, Cao Y, Hu K, et al. Radiofrequency ablation triggers the migration of hepatocellular carcinoma cells by suppressing miR-148a-5p. Biol Chem. 2020; 401(8): 985-994.

[143] Dong S, Kong J, Kong F, et al. Insufficient radiofrequency ablation promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through Akt and ERK signaling pathways. J Transl Med. 2013; 11: 273.

[144] Chen X, Huang Y, Chen H, et al. Augmented EPR effect post IRFA to enhance the therapeutic efficacy of arsenic loaded ZIF-8 nanoparticles on residual HCC progression. J Nanobiotechnology. 2022; 20(1): 34.

[145] Zhang N, Wang L, Chai ZT, et al. Incomplete radiofrequency ablation enhances invasiveness and metastasis of residual cancer of hepatocellular carcinoma cell HCCLM3 via activating β-catenin signaling. PLoS One. 2014; 9(12): e115949.

[146] Dong S, Kong J, Kong F, et al. Sorafenib suppresses the epithelial-mesenchymal transition of hepatocellular carcinoma cells after insufficient radiofrequency ablation. BMC Cancer. 2015; 15: 939.

[147] Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014; 2014: 638747.

[148] Yamada S, Utsunomiya T, Morine Y, et al. Expressions of hypoxia-inducible factor-1 and epithelial cell adhesion molecule are linked with aggressive local recurrence of hepatocellular carcinoma after radiofrequency ablation therapy. Ann Surg Oncol. 2014; 21 Suppl 3: S436-S442.

[149] Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007; 132(7): 2542-2556.

[150] Liu YC, Yeh CT, Lin KH. Cancer stem cell functions in hepatocellular carcinoma and comprehensive therapeutic strategies. Cells. 2020; 9(6): 1331.

[151] Yamashita T, Honda M, Nakamoto Y, et al. Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma. Hepatology. 2013; 57(4): 1484-1497.

[152] Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene. 2008; 27(12): 1749-1758.

[153] Gao Y, Ruan B, Liu W, et al. Knockdown of CD44 inhibits the invasion and metastasis of hepatocellular carcinoma both in vitro and in vivo by reversing epithelial-mesenchymal transition. Oncotarget. 2015; 6(10): 7828-7837.

[154] Haraguchi N, Ishii H, Mimori K, et al. CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest. 2010; 120(9): 3326-3339.

[155] Yang ZF, Ho DW, Ng MN, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell. 2008; 13(2): 153-166.

[156] Sukowati CH, Anfuso B, Torre G, Francalanci P, Crocè LS, Tiribelli C. The expression of CD90/Thy-1 in hepatocellular carcinoma: an in vivo and in vitro study. PLoS One. 2013; 8(10): e76830.

[157] Yang XR, Xu Y, Yu B, et al. CD24 is a novel predictor for poor prognosis of hepatocellular carcinoma after surgery. Clin Cancer Res. 2009; 15(17): 5518-5527.

[158] Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO. CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell. 2011; 9(1): 50-63.

[159] Lu S, Yao Y, Xu G, et al. CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma. Cell Death Dis. 2018; 9(6): 646.

[160] Lo J, Lau EY, Ching RH, et al. Nuclear factor kappa B-mediated CD47 up-regulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma in mice. Hepatology. 2015; 62(2): 534-545.

[161] Wang C, Wang MD, Cheng P, et al. Hepatitis B virus X protein promotes the stem-like properties of OV6(+) cancer cells in hepatocellular carcinoma. Cell Death Dis. 2017; 8(1): e2560.

[162] Wang S, Liu J, Wu H, et al. All-trans retinoic acid (ATRA) inhibits insufficient radiofrequency ablation (IRFA)-induced enrichment of tumor-initiating cells in hepatocellular carcinoma. Chin J Cancer Res. 2021; 33(6): 694-707.

[163] Yuan CW, Wang ZC, Liu K, Liu DJ. Incomplete radiofrequency ablation promotes the development of CD133(+) cancer stem cells in hepatocellular carcinoma cell line HepG2 via inducing SOX9 expression. Hepatobiliary Pancreat Dis Int. 2018; 17(5): 416-422.

[164] Zhang Z, Zhang Y, Zhang L, et al. Incomplete radiofrequency ablation provokes colorectal cancer liver metastases through heat shock response by PKCα/Fra-1 pathway. Cancer Biol Med. 2019; 16(3): 542-555.

[165] Wang X, Deng Q, Feng K, et al. Insufficient radiofrequency ablation promotes hepatocellular carcinoma cell progression via autophagy and the CD133 feedback loop. Oncol Rep. 2018; 40(1): 241-251.

[166] Liu K, Hao M, Ouyang Y, Zheng J, Chen D. CD133(+) cancer stem cells promoted by VEGF accelerate the recurrence of hepatocellular carcinoma. Sci Rep. 2017; 7: 41499.

[167] Cui X, Wu Y, Wang Z, Liu X, Wang S, Qin C. MicroRNA-34a expression is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma. Tumour Biol. 2015; 36(5): 3887-3893.

[168] Oura K, Morishita A, Masaki T. Molecular and functional roles of microRNAs in the progression of hepatocellular carcinoma—a review. Int J Mol Sci. 2020; 21(21): 8362.

[169] Lim LJ, Wong SYS, Huang F, et al. Roles and regulation of long noncoding RNAs in hepatocellular carcinoma. Cancer Res. 2019; 79(20): 5131-5139.

[170] Deng Q, Chen S, Fu C, et al. Long noncoding RNA expression profiles in sub-lethal heat-treated hepatoma carcinoma cells. World J Surg Oncol. 2017; 15(1): 136.

[171] Hu XY, Li L, Wu HT, Liu Y, Wang BD, Tang Y. Serum miR-130b level, an ideal marker for monitoring the recurrence and prognosis of primary hepatocellular carcinoma after radiofrequency ablation treatment. Pathol Res Pract. 2018; 214(10): 1655-1660.

[172] Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011; 146(3): 353-358.

[173] Wang J, Liu X, Wu H, et al. CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res. 2010; 38(16): 5366-5383.

[174] Cesana M, Cacchiarelli D, Legnini I, et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011; 147(2): 358-369.

[175] Li Z, Jiang M, Zhang T, Liu S. GAS6-AS2 promotes hepatocellular carcinoma via miR-3619-5p/ARL2 axis under insufficient radiofrequency ablation condition. Cancer Biother Radiopharm. 2021; 36(10): 879-887.

[176] Ma D, Gao X, Liu Z, Lu X, Ju H, Zhang N. Exosome-transferred long non-coding RNA ASMTL-AS1 contributes to malignant phenotypes in residual hepatocellular carcinoma after insufficient radiofrequency ablation. Cell Prolif. 2020; 53(9): e12795.

[177] Zeng J, Cai X, Hao X, et al. LncRNA FUNDC2P4 down-regulation promotes epithelial-mesenchymal transition by reducing E-cadherin expression in residual hepatocellular carcinoma after insufficient radiofrequency ablation. Int J Hyperthermia. 2018; 34(6): 802-811.

[178] Chen JW, Lai LS, Luo JY, et al. Identification of circRNAs involved in the development of hepatocellular carcinoma after insufficient radiofrequency ablation. Neoplasma. 2022; 69(3): 527-537.

[179] Su T, Huang M, Liao J, et al. Insufficient radiofrequency ablation promotes hepatocellular carcinoma metastasis through N6-methyladenosine mRNA methylation-dependent mechanism. Hepatology. 2021; 74(3): 1339-1356.

[180] Li K, Niu Y, Yuan Y, et al. Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-β signaling. Oncogene. 2022; 41(23): 3197-3209.

[181] Schimmel P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis. Nat Rev Mol Cell Biol. 2018; 19(1): 45-58.

[182] Zhu S, Wu Y, Zhang X, et al. Targeting N(7)-Methylguanosine tRNA modification blocks hepatocellular carcinoma metastasis after insufficient radiofrequency ablation. Mol Ther. 2022; 31(6): 1596-1614.

[183] Zeng X, Liao G, Li S, et al. Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation. Hepatology. 2022; 77(4): 1122-1138.

[184] Lee YJ, Jang BK. The role of autophagy in hepatocellular carcinoma. Int J Mol Sci. 2015; 16(11): 26629-26643.

[185] Xu WL, Wang SH, Sun WB, et al. Insufficient radiofrequency ablation-induced autophagy contributes to the rapid progression of residual hepatocellular carcinoma through the HIF-1α/BNIP3 signaling pathway. BMB Rep. 2019; 52(4): 277-282.

[186] Jiang J, Chen S, Li K, et al. Targeting autophagy enhances heat stress-induced apoptosis via the ATP-AMPK-mTOR axis for hepatocellular carcinoma. Int J Hyperthermia. 2019; 36(1): 499-510.

[187] Peng C, Li X, Ao F, et al. Mitochondrial ROS driven by NOX4 upregulation promotes hepatocellular carcinoma cell survival after incomplete radiofrequency ablation by inducing of mitophagy via Nrf2/PINK1. J Transl Med. 2023; 21(1): 218.

[188] Ciccarone F, Castelli S, Ciriolo MR. Oxidative stress-driven autophagy acROSs onset and therapeutic outcome in hepatocellular carcinoma. Oxid Med Cell Longev. 2019; 2019: 6050123.

[189] Ahmed K, Zaidi SF, Mati Ur R, Rehman R, Kondo T. Hyperthermia and protein homeostasis: cytoprotection and cell death. J Therm Biol. 2020; 91: 102615.

[190] Agarwal M, Pandita S, Hunt CR, et al. Inhibition of telomerase activity enhances hyperthermia-mediated radiosensitization. Cancer Res. 2008; 68(9): 3370-3378.

[191] Schaaf L, Schwab M, Ulmer C, et al. Hyperthermia synergizes with chemotherapy by inhibiting PARP1-dependent DNA replication arrest. Cancer Res. 2016; 76(10): 2868-2875.

[192] Roake CM, Artandi SE. Regulation of human telomerase in homeostasis and disease. Nat Rev Mol Cell Biol. 2020; 21(7): 384-397.

[193] Kumar N, Sethi G. Telomerase and hallmarks of cancer: an intricate interplay governing cancer cell evolution. Cancer Lett. 2023; 578: 216459.

[194] Zgajnar NR, De Leo SA, Lotufo CM, Erlejman AG, Piwien-Pilipuk G, Galigniana MD. Biological actions of the Hsp90-binding immunophilins FKBP51 and FKBP52. Biomolecules. 2019; 9(2): 52.

[195] Toogun OA, Dezwaan DC, Freeman BC. The hsp90 molecular chaperone modulates multiple telomerase activities. Mol Cell Biol. 2008; 28(1): 457-467.

[196] Jeong YY, Her J, Oh SY, Chung IK. Hsp90-binding immunophilin FKBP52 modulates telomerase activity by promoting the cytoplasmic retrotransport of hTERT. Biochem J. 2016; 473(20): 3517-3532.

[197] Wang X, Zhou P, Sun X, et al. Modification of the hTERT promoter by heat shock elements enhances the efficiency and specificity of cancer targeted gene therapy. Int J Hyperthermia. 2016; 32(3): 244-253.

[198] Hopkins JL, Lan L, Zou L. DNA repair defects in cancer and therapeutic opportunities. Genes Dev. 2022; 36(5-6): 278-293.

[199] Krawczyk PM, Eppink B, Essers J, et al. Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. Proc Natl Acad Sci USA. 2011; 108(24): 9851-9856.

[200] Nakagawa Y, Kajihara A, Takahashi A, et al. BRCA2 protects mammalian cells from heat shock. Int J Hyperthermia. 2018; 34(6): 795-801.

[201] Oei AL, Ahire VR, van Leeuwen CM, et al. Enhancing radiosensitisation of BRCA2-proficient and BRCA2-deficient cell lines with hyperthermia and PARP1-i. Int J Hyperthermia. 2018; 34(1): 39-48.

[202] Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005; 434(7035): 913-917.

[203] Roberts EW, Broz ML, Binnewies M, et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell. 2016; 30(2): 324-336.

[204] Liu Q, Zhai B, Yang W, et al. Abrogation of local cancer recurrence after radiofrequency ablation by dendritic cell-based hyperthermic tumor vaccine. Mol Ther. 2009; 17(12): 2049-2057.

[205] Dromi SA, Walsh MP, Herby S, et al. Radiofrequency ablation induces antigen-presenting cell infiltration and amplification of weak tumor-induced immunity. Radiology. 2009; 251(1): 58-66.

[206] Ali MY, Grimm CF, Ritter M, et al. Activation of dendritic cells by local ablation of hepatocellular carcinoma. J Hepatol. 2005; 43(5): 817-8122.

[207] Shan CC, Shi LR, Ding MQ, et al. Cytokine-induced killer cells co-cultured with dendritic cells loaded with the protein lysate produced by radiofrequency ablation induce a specific antitumor response. Oncol Lett. 2015; 9(4): 1549-1556.

[208] Nakagawa H, Mizukoshi E, Iida N, et al. In vivo immunological antitumor effect of OK-432-stimulated dendritic cell transfer after radiofrequency ablation. Cancer Immunol Immunother. 2014; 63(4): 347-356.

[209] Iida N, Nakamoto Y, Baba T, et al. Antitumor effect after radiofrequency ablation of murine hepatoma is augmented by an active variant of CC Chemokine ligand 3/macrophage inflammatory protein-1alpha. Cancer Res. 2010; 70(16): 6556-6565.

[210] Mizukoshi E, Yamashita T, Arai K, et al. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology. 2013; 57(4): 1448-1457.

[211] Zerbini A, Pilli M, Penna A, et al. Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res. 2006; 66(2): 1139-1146.

[212] Hansler J, Wissniowski TT, Schuppan D, et al. Activation and dramatically increased cytolytic activity of tumor specific T lymphocytes after radio-frequency ablation in patients with hepatocellular carcinoma and colorectal liver metastases. World J Gastroenterol. 2006; 12(23): 3716-3721.

[213] Nobuoka D, Motomura Y, Shirakawa H, et al. Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes. Int J Oncol. 2012; 40(1): 63-70.

[214] Duan XH, Li TF, Zhou GF, et al. Transcatheter arterial embolization combined with radiofrequency ablation activates CD8(+) T-cell infiltration surrounding residual tumors in the rabbit VX2 liver tumors. Onco Targets Ther. 2016; 9: 2835-2844.

[215] Milani V, Noessner E, Ghose S, et al. Heat shock protein 70: role in antigen presentation and immune stimulation. Int J Hyperthermia. 2002; 18(6): 563-575.

[216] Udono H, Ichiyanagi T, Mizukami S, Imai T. Heat shock proteins in antigen trafficking–implications on antigen presentation to T cells. Int J Hyperthermia. 2009; 25(8): 617-625.

[217] Blachere NE, Li Z, Chandawarkar RY, et al. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med. 1997; 186(8): 1315-1322.

[218] Ito F, Vardam TD, Appenheimer MM, et al. In situ thermal ablation augments antitumor efficacy of adoptive T cell therapy. Int J Hyperthermia. 2019; 36(sup1): 22-36.

[219] Zerbini A, Pilli M, Laccabue D, et al. Radiofrequency thermal ablation for hepatocellular carcinoma stimulates autologous NK-cell response. Gastroenterology. 2010; 138(5): 1931-1942.

[220] Lee HA, Goh HG, Lee YS, et al. Natural killer cell activity is a risk factor for the recurrence risk after curative treatment of hepatocellular carcinoma. BMC Gastroenterol. 2021; 21(1): 258.

[221] Mo Z, Lu H, Mo S, Fu X, Chang S, Yue J. Ultrasound-guided radiofrequency ablation enhances natural killer-mediated antitumor immunity against liver cancer. Oncol Lett. 2018; 15(5): 7014-7020.

[222] Li M, Hao B, Zhang M, et al. Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development. Signal Transduct Target Ther. 2021; 6(1): 330.

[223] Shi L, Chen L, Wu C, et al. PD-1 blockade boosts radiofrequency ablation-elicited adaptive immune responses against tumor. Clin Cancer Res. 2016; 22(5): 1173-1184.

[224] Wu H, Li SS, Zhou M, et al. Palliative radiofrequency ablation accelerates the residual tumor progression through increasing tumor-infiltrating MDSCs and reducing T-cell-mediated anti-tumor immune responses in animal model. Front Oncol. 2020; 10: 1308.

[225] Tang Y, Shu Z, Zhu M, et al. Size-tunable nanoregulator-based radiofrequency ablation suppresses MDSCs and their compensatory immune evasion in hepatocellular carcinoma. Adv Healthc Mater. 2023; 12(30): e2302013.

[226] Liu M, Zhou J, Liu X, et al. Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma. Gut. 2020; 69(2): 365-379.

[227] Lemdani K, Mignet N, Boudy V, et al. Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma. Oncoimmunology. 2019; 8(3): 1550342.

[228] Gu T, Ge Y, Song Y, et al. Hepatic radiofrequency ablation causes an increase of circulating histones in patients with hepatocellular carcinoma. Scand J Clin Lab Invest. 2015; 75(7): 621-627.

[229] Abrams ST, Zhang N, Manson J, et al. Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2013; 187(2): 160-169.

[230] Zhang Y, Peng Z, Chen M, et al. Elevated neutrophil to lymphocyte ratio might predict poor prognosis for colorectal liver metastasis after percutaneous radiofrequency ablation. Int J Hyperthermia. 2012; 28(2): 132-140.

[231] Rochigneux P, Nault JC, Mallet F, et al. Dynamic of systemic immunity and its impact on tumor recurrence after radiofrequency ablation of hepatocellular carcinoma. Oncoimmunology. 2019; 8(8): 1615818.

[232] Albini A, Bruno A, Noonan DM, Mortara L. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol. 2018; 9: 527.

[233] Gotthardt D, Putz EM, Grundschober E, et al. STAT5 is a key regulator in NK cells and acts as a molecular switch from tumor surveillance to tumor promotion. Cancer Discov. 2016; 6(4): 414-429.

[234] Kelley RK, Sangro B, Harris W, et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study. J Clin Oncol. 2021; 39(27): 2991-3001.

[235] Romagné F, André P, Spee P, et al. Preclinical characterization of 1–7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood. 2009; 114(13): 2667-2677.

[236] Bezman NA, Jhatakia A, Kearney AY, et al. PD-1 blockade enhances elotuzumab efficacy in mouse tumor models. Blood Adv. 2017; 1(12): 753-765.

[237] Ao F, Li X, Tan Y, et al. STING agonist-based hydrogel enhances immune activation in synergy with radiofrequency ablation for hepatocellular carcinoma treatment. J Control Release. 2024; 369: 296-308.

[238] Xu A, Zhang L, Yuan J, et al. TLR9 agonist enhances radiofrequency ablation-induced CTL responses, leading to the potent inhibition of primary tumor growth and lung metastasis. Cell Mol Immunol. 2019; 16(10): 820-832.

[239] Liu J, Li X, Chen J, et al. Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma. J Nanobiotechnology. 2024; 22(1): 338.

[240] Zeng X, Ward SE, Zhou J, Cheng ASL. Liver immune microenvironment and metastasis from colorectal cancer-pathogenesis and therapeutic perspectives. Cancers (Basel). 2021; 13(10): 2418.

[241] Shi ZR, Duan YX, Cui F, et al. Integrated proteogenomic characterization reveals an imbalanced hepatocellular carcinoma microenvironment after incomplete radiofrequency ablation. J Exp Clin Cancer Res. 2023; 42(1): 133.

[242] Zhang R, Lin XH, Ma M, et al. Periostin involved in the activated hepatic stellate cells-induced progression of residual hepatocellular carcinoma after sublethal heat treatment: its role and potential for therapeutic inhibition. J Transl Med. 2018; 16(1): 302.

[243] Peng ZW, Zhang YJ, Chen MS, et al. Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial. J Clin Oncol. 2013; 31(4): 426-432.

[244] Peng ZW, Zhang YJ, Liang HH, Lin XJ, Guo RP, Chen MS. Recurrent hepatocellular carcinoma treated with sequential transcatheter arterial chemoembolization and RF ablation versus RF ablation alone: a prospective randomized trial. Radiology. 2012; 262(2): 689-700.

[245] Cheng X, Zhang H, Hamad A, Huang H, Tsung A. Surgery-mediated tumor-promoting effects on the immune microenvironment. Semin Cancer Biol. 2022; 86(Pt 3): 408-419.

[246] Scaife CL, Curley SA, Izzo F, et al. Feasibility of adjuvant hepatic arterial infusion of chemotherapy after radiofrequency ablation with or without resection in patients with hepatic metastases from colorectal cancer. Ann Surg Oncol. 2003; 10(4): 348-354.

[247] Chen K, Chen G, Wang H, et al. Increased survival in hepatocellular carcinoma with iodine-125 implantation plus radiofrequency ablation: a prospective randomized controlled trial. J Hepatol. 2014; 61(6): 1304-1311.

[248] Bian H, Zheng JS, Nan G, et al. Randomized trial of [131I] metuximab in treatment of hepatocellular carcinoma after percutaneous radiofrequency ablation. J Natl Cancer Inst. 2014; 106(9): dju239.

[249] Shi C, Li Y, Geng L, et al. Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: A randomised controlled trial. Eur J Cancer. 2022; 166: 176-184.

[250] Tak WY, Lin SM, Wang Y, et al. Phase III HEAT study adding lyso-thermosensitive liposomal doxorubicin to radiofrequency ablation in patients with unresectable hepatocellular carcinoma lesions. Clin Cancer Res. 2018; 24(1): 73-83.

[251] Kan X, Jing Y, Wan QY, et al. Sorafenib combined with percutaneous radiofrequency ablation for the treatment of medium-sized hepatocellular carcinoma. Eur Rev Med Pharmacol Sci. 2015; 19(2): 247-255.

[252] Lee JH, Lee Y, Lee M, et al. A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma. Br J Cancer. 2015; 113(12): 1666-1676.

[253] Lee JH, Lee JH, Lim YS, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. 2015; 148(7): 1383-1391.e6.

[254] Pan YX, Xi M, Fu YZ, et al. Stereotactic body radiotherapy as a salvage therapy after incomplete radiofrequency ablation for hepatocellular carcinoma: a retrospective propensity score matching study. Cancers (Basel). 2019; 11(8): 1116.

[255] Hamamoto S, Okuma T, Yamamoto A, et al. Radiofrequency ablation and immunostimulant OK-432: combination therapy enhances systemic antitumor immunity for treatment of VX2 lung tumors in rabbits. Radiology. 2013; 267(2): 405-413.

[256] Sun T, Sun B, Cao Y, et al. Synergistic effect of OK-432 in combination with an anti-PD-1 antibody for residual tumors after radiofrequency ablation of hepatocellular carcinoma. Biomed Pharmacother. 2023; 166: 115351.

[257] Sun B, Zhang Q, Sun T, et al. Radiofrequency hyperthermia enhances the effect of OK-432 for Hepatocellular carcinoma by activating of TLR4-cGAS-STING pathway. Int Immunopharmacol. 2024; 130: 111769.

[258] Iwai T, Oebisu N, Hoshi M, et al. Promising abscopal effect of combination therapy with thermal tumour ablation and intratumoural OK-432 injection in the rat osteosarcoma model. Sci Rep. 2020; 10(1): 9679.

[259] Tian Z, Hu Q, Sun Z, et al. A booster for radiofrequency ablation: advanced adjuvant therapy via in situ nanovaccine synergized with anti-programmed death ligand 1 immunotherapy for systemically constraining hepatocellular carcinoma. ACS Nano. 2023; 17(19): 19441-19458.

[260] Li M, Jiang A, Han H, et al. A trinity nano-vaccine system with spatiotemporal immune effect for the adjuvant cancer therapy after radiofrequency ablation. ACS Nano. 2024; 18(5): 4590-4612.

[261] Yang Z, Zhu Y, Dong Z, et al. Tumor-killing nanoreactors fueled by tumor debris can enhance radiofrequency ablation therapy and boost antitumor immune responses. Nat Commun. 2021; 12(1): 4299.

[262] Shao YL, Arjun B, Leo HL, Chua KJ. Nano-assisted radiofrequency ablation of clinically extracted irregularly-shaped liver tumors. J Therm Biol. 2017; 66: 101-113.

[263] LeVeen R. Laser hyperthermia and radiofrequency ablation of hepatic lesions. Semin Intervent Radiol. 1997;(14): 313-324.

[264] Steeves RA. Hyperthermia in cancer therapy: where are we today and where are we going? Bull NY Acad Med. 1992; 68(2): 341-350.

[265] Nagata Y, Hiraoka M, Nishimura Y, et al. Clinical results of radiofrequency hyperthermia for malignant liver tumors. Int J Radiat Oncol Biol Phys. 1997; 38(2): 359-365.

[266] Siperstein AE, Rogers SJ, Hansen PD, Gitomirsky A. Laparoscopic thermal ablation of hepatic neuroendocrine tumor metastases. Surgery. 1997; 122(6):1147-54; discussion 1154-1155.

[267] Goldberg SN, Gazelle GS, Solbiati L, et al. Ablation of liver tumors using percutaneous RF therapy. AJR Am J Roentgenol. 1998; 170(4): 1023-1028.

[268] Lencioni R, Goletti O, Armillotta N, et al. Radio-frequency thermal ablation of liver metastases with a cooled-tip electrode needle: results of a pilot clinical trial. Eur Radiol. 1998; 8(7): 1205-1211.

[269] Scudamore CH, Lee SI, Patterson EJ, et al. Radiofrequency ablation followed by resection of malignant liver tumors. Am J Surg. 1999; 177(5): 411-417.

[270] Goldberg SN, Gazelle GS, Compton CC, Mueller PR, Tanabe KK. Treatment of intrahepatic malignancy with radiofrequency ablation: radiologic-pathologic correlation. Cancer. 2000; 88(11): 2452-2463.

[271] Feng K, Yan J, Li X, et al. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol. 2012; 57(4): 794-802.

[272] Kim YS, Lim HK, Rhim H, et al. Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular carcinoma: analysis of prognostic factors. J Hepatol. 2013; 58(1): 89-97.

[273] Siperstein AE, Berber E, Ballem N, Parikh RT. Survival after radiofrequency ablation of colorectal liver metastases: 10-year experience. Ann Surg. 2007; 246(4):559-65; discussion 565-567.

[274] Ruers T, Van Coevorden F, Punt CJ, et al. Local treatment of unresectable colorectal liver metastases: results of a randomized phase II trial. J Natl Cancer Inst. 2017; 109(9): djx015.

[275] Huang HC, Gatchalian LB, Hsieh YC, Chen WT, Lin CC, Lin SM. Real-time virtual sonography-assisted radiofrequency ablation in liver tumors with conspicuous or inconspicuous images or peritumoral landmarks under ultrasonography. Abdom Radiol (NY). 2021; 46(6): 2814-2822.

[276] Tanis E, Spliethoff JW, Evers DJ, et al. Real-time in vivo assessment of radiofrequency ablation of human colorectal liver metastases using diffuse reflectance spectroscopy. Eur J Surg Oncol. 2016; 42(2): 251-259.

[277] Besler E, Wang YC, Sahakian AV. Early and late fusion machine learning on multi-frequency electrical impedance data to improve radiofrequency ablation monitoring. IEEE J Biomed Health Inform. 2020; 24(8): 2359-2367.

[278] Aref MH, Aboughaleb IH, Youssef AM, El-Sharkawy YH. Hyperspectral image-based analysis of thermal damage for ex-vivo bovine liver utilizing radiofrequency ablation. Surg Oncol. 2021; 38: 101564.

[279] Cheng Z, Wang Y, Yuan M, et al. CT perfusion imaging can detect residual lung tumor early after radiofrequency ablation: a preliminary animal study on both tumoral and peri-tumoral region assessment. J Thorac Dis. 2022; 14(1): 64-75.

[280] Zheng JH, Chang ZH, Han CB, et al. Detection of residual tumor following radiofrequency ablation of liver metastases using 18F-FDG PET/PET-CT: a systematic review and meta-analysis. Nucl Med Commun. 2014; 35(4): 339-346.

[281] Hoeffel C, Pousset M, Timsit MO, et al. Radiofrequency ablation of renal tumours: diagnostic accuracy of contrast-enhanced ultrasound for early detection of residual tumour. Eur Radiol. 2010; 20(8): 1812-1821.

[282] Boysen AK, Pallisgaard N, Andersen CSA, Spindler KG. Circulating tumor DNA as a marker of minimal residual disease following local treatment of metastases from colorectal cancer. Acta Oncol. 2020; 59(12): 1424-1429.

[283] Parameswaran R, Al-Kaisey AM, Kalman JM. Catheter ablation for atrial fibrillation: current indications and evolving technologies. Nat Rev Cardiol. 2021; 18(3): 210-225.

[284] Nieuwenhuizen S, Puijk RS, van den Bemd B, et al. Resectability and ablatability criteria for the treatment of liver only colorectal metastases: multidisciplinary consensus document from the COLLISION Trial Group. Cancers (Basel). 2020; 12(7): 1779.

[285] Li X, Dai X, Shi L, et al. Phase II/III study of radiofrequency ablation combined with cytokine-induced killer cells treating colorectal liver metastases. Cell Physiol Biochem. 2016; 40(1-2): 137-145.

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